(2R,3S,4R,5R)-2-(4-amino-2-oxopyrimidin-1(2H)-yl)-5-(((tert-butoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyl di-tert-butyl bis(carbonate) | 1257411-75-8

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: (2R,3S,4R,5R)-2-(4-amino-2-oxopyrimidin-1(2H)-yl)-5-(((tert-butoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyl di-tert-butyl bis(carbonate)
• CAS: 1257411-75-8
• 化学式: C₂₄H₃₇N₃O₁₁
• 分子量: 543.571
• InChiKey: KVPNUUFXPVRIEY-MXASKKJJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.32
• 重原子数：
  38.0
• 可旋转键数：
  5.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  176.73
• 氢给体数：
  1.0
• 氢受体数：
  14.0

反应信息

• 作为反应物：
  描述：

  (2R,3S,4R,5R)-2-(4-amino-2-oxopyrimidin-1(2H)-yl)-5-(((tert-butoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyl di-tert-butyl bis(carbonate) 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 74.5h， 生成 2-(6,8-dichloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N-(1-((2R,3S,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide
  参考文献：
  名称：

  Translocator Protein (TSPO) Ligand−Ara-C (Cytarabine) Conjugates as a Strategy To Deliver Antineoplastic Drugs and To Enhance Drug Clinical Potential

  摘要：

  The aim of this work was to evaluate TSPO ligand-Ara-C conjugation as an approach for the selective delivery of the antineoplastic agent to brain tumors as well as for overcome P-gp resistance induction observed for the majority of cytotoxic agents, enhancing the drug clinical potential. To this end, the novel N-imidazopyridinacetyl-Ara-C conjugates 3a-c, 10 and 15 have been prepared and evaluated for their cytotoxicity against glioma cell lines. In contrast to that observed for 3a-c and 10, the conjugate 15 resulted stable in both phosphate buffer and physiological medium. In all cases, the release of free Ara-C from hydrolyzed conjugates was checked by HPLC and ESI-MS analysis. Conjugates 10 and 15 displayed very high in vitro TSPO affinity and selectivity, and, hence, they may possess potential for targeted brain delivery. Due to the favorable features displayed by the conjugate 15, it was further evaluated on glioma cell lines, expressing high levels of TSPO, in the presence and in the absence of specific nucleoside transport (NT) inhibitors. In contrast to that observed for the free Ara-C, the presence of NT inhibitors did not reduce the cytotoxic activity of 15. Moreover, conjugate 15, as N-4-acyl derivative of Ara-C, should be resistant to inactivation by cytidine deaminase, and it may possess enhanced propensity to target brain tumor cells characterized by a reduced expression of NTs. In addition, this conjugate behaves as a clear P-gp modulator and thereby may be useful to reverse MDR. Transport studies across the MDCKII-MDR1 monolayer indicated that conjugate 15 should overcome the BBB by transcellular pathway. All these features may be useful for enhancing the clinical potential of the nucleoside drug Ara-C.

  DOI：

  10.1021/mp100235w
• 作为产物：
  描述：

  二碳酸二叔丁酯 、 盐酸阿糖胞苷 在 potassium hydroxide 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 17.0h， 以48%的产率得到(2R,3S,4R,5R)-2-(4-amino-2-oxopyrimidin-1(2H)-yl)-5-(((tert-butoxycarbonyl)oxy)methyl)tetrahydrofuran-3,4-diyl di-tert-butyl bis(carbonate)
  参考文献：
  名称：

  Translocator Protein (TSPO) Ligand−Ara-C (Cytarabine) Conjugates as a Strategy To Deliver Antineoplastic Drugs and To Enhance Drug Clinical Potential

  摘要：

  The aim of this work was to evaluate TSPO ligand-Ara-C conjugation as an approach for the selective delivery of the antineoplastic agent to brain tumors as well as for overcome P-gp resistance induction observed for the majority of cytotoxic agents, enhancing the drug clinical potential. To this end, the novel N-imidazopyridinacetyl-Ara-C conjugates 3a-c, 10 and 15 have been prepared and evaluated for their cytotoxicity against glioma cell lines. In contrast to that observed for 3a-c and 10, the conjugate 15 resulted stable in both phosphate buffer and physiological medium. In all cases, the release of free Ara-C from hydrolyzed conjugates was checked by HPLC and ESI-MS analysis. Conjugates 10 and 15 displayed very high in vitro TSPO affinity and selectivity, and, hence, they may possess potential for targeted brain delivery. Due to the favorable features displayed by the conjugate 15, it was further evaluated on glioma cell lines, expressing high levels of TSPO, in the presence and in the absence of specific nucleoside transport (NT) inhibitors. In contrast to that observed for the free Ara-C, the presence of NT inhibitors did not reduce the cytotoxic activity of 15. Moreover, conjugate 15, as N-4-acyl derivative of Ara-C, should be resistant to inactivation by cytidine deaminase, and it may possess enhanced propensity to target brain tumor cells characterized by a reduced expression of NTs. In addition, this conjugate behaves as a clear P-gp modulator and thereby may be useful to reverse MDR. Transport studies across the MDCKII-MDR1 monolayer indicated that conjugate 15 should overcome the BBB by transcellular pathway. All these features may be useful for enhancing the clinical potential of the nucleoside drug Ara-C.

  DOI：

  10.1021/mp100235w